Cancer Cell Metastasis: From Molecular Mechanisms to Therapeutic Strategies

ABSTRACT Cancer metastasis is a spatiotemporal dynamic process jointly driven by the intrinsic evolution of cancer cells and continuous microenvironmental selection, rather than a simple linear accumulation of genetic alterations. The metastatic diversity of cancers is driven by heterogeneity in physicochemical properties, cellular composition, and signaling networks among primary tumors, dissemination routes, and target organs. Currently, the stage‐dependent and route‐dependent molecular mechanisms underlying metastasis and potential pan‐cancer therapeutic targets remain incompletely defined. Here, we systematically discuss the genomic, chromosomal, and epigenetic evolution of metastatic tumor cells (MTCs) following their spatiotemporal trajectory from in situ evolution to metastatic colonization. We describe their migration behaviors and interaction patterns within the migratory tumor microenvironment across hematogenous, lymphatic, and perineural routes, and the establishment and remodeling of organ‐specific metastatic niches. We also review the progress and limitations of metastasis‐oriented diagnostic stratification and therapeutic interventions. We argue for the shift of antimetastatic strategies from target‐centric approaches to precise interventions that match timing, routes, biomarkers, and endpoints. By integrating the molecular mechanisms underlying spatiotemporal changes during cancer metastasis, this review delineates the spatiotemporal evolutionary landscape of metastasis and the MTC–microenvironment interaction patterns, thereby offering insights for future clinical translation of metastasis‑targeted therapies.